PK/PD "PK/PD of quinolones: from basics (not too much) to registration and clinical implications. Paul M. Tulkens Françoise Van Bambeke Unité de pharmacologie cellulaire et moléculaire Université catholique de Louvain, Bruxelles PK/PD - Budapest 23-04-05

PK/PD "PK/PD of quinolones: from basics (not too much) to registration and clinical implications. Paul M. Tulkens Françoise Van Bambeke Unité de pharmacologie cellulaire et moléculaire Université catholique de Louvain, Bruxelles Don't be jealous, this is NOT our lab… PK/PD - Budapest 23-04-05

at at a reasonable cost … Why do we need quinolones for (and all antibiotics) in the first place ? Efficacy ... at at a reasonable cost … PK/PD - Budapest 23-04-05

Cost is not too bad nowadays… PK/PD - Budapest 23-04-05

May be, this is why … PK/PD - Budapest 23-04-05

Efficacy of ciprofloxacin will not be too bad for Gram(-) bugs If you get a AUC24h / MIC > 125 Forrest et al., AAC, 1993 PK/PD - Budapest 23-04-05

And that of levofloxacin for S. pneumoniae not bad either … If you get a peak / MIC > 12 Preston et al., JAMA. 1998 279:125-9. PK/PD - Budapest 23-04-05

To finish on this … Modelling studies show that survival (= efficacy ...) for FQ is linked mainly to Peak/MIC when > 10/1 is more linked to AUC/MIC when peak / MIC is < 10/1 Then, in the absence of a high peak ... AUC/MIC ratio must be > 125 for all Gram (-) AUC/MIC ratio can be 30 for Gram(+) if host is healthy but with immunocompromised hosts , AUC/MIC for Gram(+) organisms is better > 125 ... PK/PD - Budapest 23-04-05

But is efficacy all we want from quinolones ? We want eradication ... PK/PD - Budapest 23-04-05

Which is the most basic pharmacological property of quinolones in comparison with most other antibiotics … ? PK/PD - Budapest 23-04-05

They kill FAST and in a CONCENTRATION-dependent manner ! Which is the most basic pharmacological property of quinolones in comparison with most other antibiotics … ? They kill FAST and in a CONCENTRATION-dependent manner ! PK/PD - Budapest 23-04-05

But what is their downside ? Résistance … S. pneumoniae 1.2 Levofloxacin Gatifloxacin 1.0 0.8 Percent 0.6 0.4 0.2 0.0 1997 1998 1999 2000 2001 Year From: Canadian Bacterial Surveillance Network. PK/PD - Budapest 23-04-05

Resistance IS a problem for P. aeruginosa … MIC distributions in Belgium … J. van Eldere, 2003 PK/PD - Budapest 23-04-05

1. Mutations (and this may be why …) Why resistance ? Persistent RecA-ssDNA filaments induce levels of LexA cleavage sufficient to de-repress the error prone polymerases, Pol IV and Pol V, which cooperate to induce mutations (pathway D). 1. Mutations (and this may be why …) Cirz RT, Chin JK, Andes DR, de Crécy-Lagard V, Craig WA, et al. (2005) Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biol 3(6):e176. PK/PD - Budapest 23-04-05

Mutant Prevention Concentration … Bactericidal effect of a FQ towards Mycobacterium bovis 1 MIC 99 = 0.8 10 -2 "Classic" bactericidal effect 10 -4 overlevenden 10 -6 10 -8 MPC 10 = 9 Elimination of first mutants 10 -10 0.01 0.10 1.00 10.00 concentratie Dong et al; AAC 43:1756-1758 PK/PD - Budapest 23-04-05

Mutant Prevention Concentration … Concentration which will inhibit the majority of the organisms 1 MIC 99 = 0.8 10 -2 10 -4 overlevenden Concentratie necessary to prevent the selection of the first mutants 10 -6 10 -8 MPC 10 = 9 10 -10 0.01 0.10 1.00 10.00 concentratie Dong et al; AAC 43:1756-1758 PK/PD - Budapest 23-04-05

"Window" where the selection of mutants takes place … Mutation selection window MPC concentratie MSW MIC Tijd na toediening concept overgenomen van Drlica & Zhao, Rev. Med. Microbiol. 2004, 15:73-80 PK/PD - Budapest 23-04-05

"Window" where the selection of mutants takes place … Eradication of the first mutants MPC concentratie MSW Selection of the first mutantes MIC No therapeutic effect Tijd na toediening concept overgenomen van Drlica & Zhao, Rev. Med. Microbiol. 2004, 15:73-80 PK/PD - Budapest 23-04-05

Why resistance in Gram - ? 2. Decreased entry susceptible bacteria porin periplasm cytosol PK/PD - Budapest 23-04-05

Why resistance in Gram - ? 2. Decreased entry Less susceptible ... porin periplasm cytosol PK/PD - Budapest 23-04-05

3. Efflux (and this an example of how it works in Gram (-) Why resistance ? 3. Efflux (and this an example of how it works in Gram (-) resistant bacteria susceptible bacteria pore expressed in wild-type strains! MexB MexA OprM porin periplasm lipoprotein H+ pump cytosol PK/PD - Budapest 23-04-05

2. Efflux (and this why it is dangerous … Why resistance ? 2. Efflux (and this why it is dangerous … -lac ML TET AG FQ Chl MexAB-OprM MexCD-OprJ MexEF-OprN MexHI-OprD MexJK-OprM MexXY-OprM constitutive expression inducible expression Van Bambeke et al. JAC (2003) 51:1055-65; Aeschlimann, Pharmacotherapy (2003) 23:916-24 PK/PD - Budapest 23-04-05

Efflux and mutations work together to bring the sensitivity of the organism above the berakpoint … MIC 2e mut. 2e mut. 1e mut. ciprofloxacin Limiet voor gevoeligheid 1e mut. wild wild w/o efflux with efflux PK/PD - Budapest 23-04-05

Eradication is therefore less easy than you tought ... Eradication must be geared towards Sensitive bacteria (wild type) Mutants Efflux pumps overexpressers PK/PD - Budapest 23-04-05

peak / MIC > 10 and/or > MPC Let us do the exercise … Prevention of resistance AND efficacy: peak / MIC > 10 and/or > MPC AUC / MIC > 100 (niet volledig immuuncompetente patiënt) PK/PD - Budapest 23-04-05

Moxifloxacin Levofloxacin Cumulative distribution van MIC for S. pneumoniae in Belgium S.pneumoniae 2a 120,00% Moxifloxacin 100,00% 80,00% 60,00% 40,00% Levofloxacin 20,00% ,00% 0,002 0,004 0,008 0,015 0,03 0,06 0,12 0,25 0,5 1 2 4 8 16 32 64 128 256 Moxifloxacine Levofloxacine Ciprofloxacine Clarithromycine Doxycycline J.Verhaegen et al. ECCMID 2003 PK/PD - Budapest 23-04-05

PK/PD in action … Levofloxacin 500 mg 1X / day AUC [(mg/l)xh] 47 Kritisch punt PK/PD 20 40 60 80 100 0.015 0.03 0.06 0.125 0.25 0.5 1 2 4 MIC % gevoelige stammen Levofloxacin 500 mg 1X / day AUC [(mg/l)xh] 47 peak [mg/l] 5 MICmax < 0.5 moxi levo Moxifloxacin 400 mg 1X /day AUC [(mg/l)xh] 48 peak [mg/l] 4.5 MICmax < 0.5 MIC data: J. Verhaegen et al., 2003 PK/PD - Budapest 23-04-05

Kunnen we de oefening maken voor P. aeruginosa? Verdeling van de MIC-waarden van P. aeruginosa 50 100 150 0,02 0,06 0,19 PK/PD-limiet voor levo 500 mg: meer dan 60 % van de stammen die "gevoelig" genoemd worden ontsnappen… 4 12 32 0,5 1,5 J. van Eldere, 2003 oflox levo cipro PK/PD - Budapest 23-04-05

Kunnen we de oefening maken in België? Verdeling van de MIC-waarden van P. aeruginosa Levo 1000 mg: 30 % van de stammen die "gevoelig" genoemd worden ontsnappen nog steeds... J. van Eldere, 2003 PK/PD - Budapest 23-04-05

Et pour la cipro … v-à-v de Pseudomonas …en Belgique ? Distribution des CMI de Ps. aeruginosa Cipro 1200 mg PK/PD - Budapest 23-04-05

Therefore, new breakpoints … Van Bambeke F, Michot JM, Van Eldere J, Tulkens PM. Quinolones in 2005: an update. Clin Microbiol Infect. 2005 Apr;11(4):256-80. PMID: 15760423 PK/PD - Budapest 23-04-05

Rational principles for choosing a fluoroquinolone Know your local epidemiology… get MIC-distributions … Compute (or have someone computing for you) the PK profile that will ensure > 90 % efficacy and prevention of resistance for the organims you are facing (in terms of peaks and AUC) get some safety margin (MPC …) Compare the offers … PK/PD - Budapest 23-04-05

I hope you enjoyed… and we thank … The Belgian surrealism… W.A. Craig, MD MMM. Dudley, Pharm. G.L. Drusano, MD J.J. Schentag, Pharm. A. McGowan, MD X. Zao, PhD V. Firsov, MD S. Zinner, MD A. Dalhoff, PhD ... The Belgian peaks and troughs … www.isap.org PK/PD - Budapest 23-04-05